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The impact of insulin

Cost-effective diabetes therapies are needed to alleviate the financial burden

Face of a young girl painted with a world map The International Diabetes Foundation (IDF) says that diabetes affects about 250 million people worldwide, and the number is expected to rise to 380 million by 2025. Globally, the disease was responsible for about 3.8 million deaths in 2007.

The underlying causes remain unknown, but those with type 1 diabetes cannot produce insulin and those with type 2 may produce insufficient or ineffective insulin, or the liver may produce excess glucose which leads to hyperglycaemia.

The IDF estimates that at least $232bn was spent on the prevention and treatment of diabetes and its complications in 2007. By 2025, this will reach $302.5bn. Europe accounts for a quarter of the annual worldwide treatment cost leading to a  search for efficacious and cost-effective therapies. To date this has primarily comprised insulin and sulphonylureas.

Lantus (insulin glargine), a subcutaneous recombinant human insulin analog from sanofi-aventis, has been on the market since 2000 and achieved sales worth $2.79bn in 2007.

Novolog (insulin aspart), a rapid, short-acting human insulin analog also launched in 2000 by Novo Nordisk, brought in revenues in 2007 totalling $2.09bn. The company has modified the product into the more user-friendly formulations: NovoMix 30 is a dual-release insulin analog formulation of one rapid- and one intermediate-acting form of insulin aspart delivered in a single injection, and NovoMix 50 and 70 are premixes of the rapid-acting insulin aspart for delivery three-times daily.  

Emerging pharma/biotech companies have been evaluating novel formulations and delivery methods for insulin.

Gel formulations
Australian company, Phosphagenics, has completed a phase 2 trial in type 2 patients of TPM/Insulin, a transdermal gel formulation. A US phase 2 study for type 1 diabetes is expected late in 2008. Phase 1 data showed a single dose, after overnight fasting, penetrated the skin. Drug activity was maintained for at least six hours, significantly lowering blood glucose levels

Oramed Pharmaceuticals is advancing two insulin formulations. ORMD-0801, an oral gel capsule licensed from the Israeli Hadasit technology transfer company, has undergone a phase 2a trial with positive results. Oramed has also developed systemic rectal suppository formulation,  due to complete phase I trials in the third quarter of 2008.

Intranasal delivery
Nasal delivery of insulin is believed to offer faster onset than injection and a better therapeutic avenue to those with type 2 diabetes with adequate insulin stores, but a slow post-meal insulin response. Pfizer's Exubera, a macromolecular inhaled insulin developed with Nektar Therapeutics' delivery technology launched  in 2006, first in Germany and Ireland, then in UK and US. It was for type 2 diabetes not controlled by oral agents and requiring insulin therapy, and for type 1 diabetes in combination with long- or intermediate-acting injectable insulin. Doubts over safety, dosing errors and difficulties with smokers, children and lung disease patients, combined with a product label warning over incidence of pulmonary carcinoma, resulted in poor sales. Pfizer withdrew it in October 2007. This had a negative impact on other inhaled insulin programmes: Eli Lilly and Alkermes discontinued their AIR Insulin programme and Novo Nordisk it's AERx-iDMS system.

MDRNA Inc (formerly Nastech) reported data, on its fast-acting intranasal insulin, from five patients in phase 2 trial, at the American Diabetes Association scientific sessions in June 2008. They showed the drug was well tolerated and improved glycaemic control without risk of hypoglycaemia. It attained peak plasm concentrations more rapidly than Exubera. The company is currently looking for a partner.

New therapies
According to Thomson Pharma, revenues for  human insulins will drop from $10.24bn in 2007 to $8.95bn in 2011. Further insights into other pathways and mechanisms involved in the disease's pathogenesis, offer other therapeutic avenues to explore. These include the incretin hormone glucagon-like peptide-1 (GLP-1) agonists and analogs and their dipeptidyl peptidase IV (DPP-IV) inhibitory modulators. Research is ongoing into glucokinase activators and stem cell-based therapies and monoclonal antibodies are also being assessed.

GLP-1 analogs and agonists
The hormone GLP-1 is released into the bloodstream in response to meals. It stimulates insulin secretion, delays gastric emptying, curbs appetite, promotes pancreatic beta-cell regeneration and delays their apoptosis. GLP-1 agonists and analogs bind to the membrane GLP receptors and stimulate an increase in glucose-dependent insulin secretion from pancreatic beta-cells. This could prove beneficial in treating type 1 diabetes.

According to Thomson Pharma, the GLP-1 analogs brought in $0.70bn worth of sales in 2007, forecast to rise to $1.45bn in 2011. The market leader Byetta (exenatide) is a 39-amino acid, injectable GLP-1 agonist derived from the saliva of the Gila monster lizard (Heloderma suspectum). Launched by Amylin Pharmaceuticals and Eli Lilly in the EU in 2007, Byetta is an adjunctive therapy for those with type 2 diabetes taking metformin, a sulphonylurea, a TZD, or a metformin + TZD combination. It has shown sustained blood sugar control and improved beta-cell function, is more convenient to take than insulin and offers potential for clinically significant weight loss.

Byetta's 2007 sales were $0.64bn, but, as a new therapy cost counts against it. In Italy Byetta was only available from diabetes specialists. Nevertheless, experts believe that this class of drugs has potential as a monotherapy and in combination with insulins or a DPP-IV inhibitor (see below).

Amylin and Lilly are developing a long-acting formulation, exenatide LAR, expected to reach the market in 2009, and has a nasal spray formulation in Phase 1 trials. In a comparator study, exenatide LAR reduced HbA1c levels by 1.9 per cent, compared with a 1.5 per cent with Byetta. About three out of four subjects treated with exenatide LAR achieved a haemoglobin A1C (HbA1c) level of less than 7 per cent. No major or severe hypoglycaemia was reported, and patients experienced relatively less nausea than those on Byetta.

Phase 1 data for the nasal exenatide formulation show serum levels increase dose-dependently, and therapeutic levels are seen over 3 hours at a dose of 600 micrograms. Adverse effects did not affect bioavailability.

DPP-IV inhibitors
Hot on the heels of Byetta is Merck's Januvia (sitagliptin), the first DPP-IV inhibitor launched in the US in 2006 and in several European countries by April 2008. This is an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The enzyme DPP-IV degrades GLP-1; therefore, DPP-IV inhibitors work by increasing blood levels of GLP-1, which increases insulin secretion and decreases blood glucose levels. The once-daily oral dosing gives it an advantage over injectable GLP-1 analogs, it is competitive in price and in its efficacy and tolerability profile. Pooled data from four phase 3 trials showed no significant increase in hypoglycaemia or weight gain, compared with placebo.

Januvia's competition is likely to be Bristol-Myers Squibb and AstraZeneca's Onglyza (saxagliptin). Regulatory filings have been made to the US FDA and the EMEA for the once-daily treatment of type 2 diabetes. Phase 3 data demonstrated that the DPP-IV inhibitor results in significant decreases in A1c, fasting plasma glucose and post-prandial glucagon levels and that it increases post-prandial insulin and C-peptide levels. The drug was well tolerated and weight neutral with no increase in hypoglycaemia incidence.

Glucokinase activators
Glucokinase activators lower blood glucose by stimulating insulin secretion from pancreatic beta-cells and glucose metabolism in hepatocytes. Roche Holding AG, Banyu Pharmaceutical Co Ltd and AstraZeneca plc all actively investigating the therapeutic potential of their glucokinase activator programmes.

Stem cell-based therapies
Stem cell therapies are based on either mesenchymal stem cells (MSC) or human embryonic stem (hES) cells. Osiris is evaluating Prochymal (OTI-010), a donor-derived MSC therapy, in a phase 2 trial for type 1 diabetes. The treatment involves the repopulation of bone marrow in those with type 1 diabetes by intravenous infusion with MSCs from a  donor. The therapy is also being investigated for graft versus host disease,

Crohn's disease and COPD
Opexa Therapeutics is investigating autologous pluripotent monocyte-derived stem cells for their ability to differentiate into pancreatic islet beta-cells which express PDX-1, insulin, glucose transporter 2, glucagon and somatostatin and which upregulate genes modulating insulin receptors, insulin receptor substrates, glucagon receptors, GLP-1 receptors, neuroD and Glut4.receptor substrates, glucagon receptors, GLP-1 receptors, neuroD and Glut4.

Monoclonal antibodies
Tolerx and GSK are developing otelixizumab, an intravenous anti-CD3 humanised version of the monoclonal antibody (mAb) YTH-12.5. A North American and European phase 3 trial in adults with type 1 diabetes began in May 2008 with the aim of assessing the ability of a single course of otelixizumab to reduce the amount of insulin required for blood glucose control.

The US Juvenile Diabetes Research Foundation (JDRF) has provided $2m funding for a pivotal, multinational, phase 2/3 clinical trial of Eli Lilly-Macrogenics' teplizumab, a non-FcR binding anti-CD3 mAb. The trial will determine if the mAb slows the progression of type 1 diabetes in children and newly-diagnosed adults.

Future developments
The development of combination products which will not only address the primary defect in the disease – a lack or malfunctioning of insulin metabolism – but also address other factors involved in the disease's pathogenesis, is likely. Diabetes is associated with other disorders such as obesity, hypertension, hyperlipidaemia and atherosclerosis and the future may bring  a single pill that tackles all these indications. Inroads are already being made in the case of (OSI) Prosidion's PSN-821, the lead in a series of G protein-coupled receptor 119 (GPR119) agonists, which has begun clinical testing for obesity and diabetes. GPR119 (also known as glucose dependent insulinotropic receptor) stimulates incretin hormone release and glucose-dependent insulin release from pancreatic beta-cells.  

The Author
Saloni Shah is managing editor of Drug Information News at Thomson Reuters

9th December 2008


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